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Abiraterone acetate


BCS Formulation F (%) PK Variability (coeffi cient of variation, CV%)14,15


Class IV Tablet


Inter-subject 61.1% Intra-subject 71.3%


Enzalutamide Class II Dissolved in caprylocaproyl macrogolglycerides (CCMG) and encapsulated in soft capsule


84% Inter-subject ≤30 %


Table 1. Profi le comparison of abiraterone acetate and enzalutamide Food Eff ect


50% Relative bioavailability for the modifi ed fasting state


• Formulation in olive oil increased exposure 4.5-fold • 2-4.4 fold increase in exposure when administered with high-fat meal to cancer patients • Recommended to take under fasting conditions


• Moderate food eff ect on rate but not extent of absorption


Drug-Drug Interactions Substrate Inhibitor


CYP3A4 (minor) SULT2A1 (major)


CYP2D6 (strong) CYP2C8 (moderate) CYP1A2 (weak) CYP2C8 (weak)


Inducer


CYP2C8 CYP3A4/5


CYP2C8 (weak) P-gp (in vitro)


CYP3A4 (strong) CYP2C19 (moderate) CYP2C9 (moderate) CYP2D6 (moderate) CYP1A2 (weak)


has a high bioavailability, low inter-subject variability, linear dose response, and no food eff ect. Therefore, the pharmacokinetic profi le is likely to be more predictable.


Current Market Landscape For Lipid Based Drug Delivery Systems


Lipid formulations have the longest commercial success track record among enabling technologies measured by the number of NDAs. There are numerous benefi ts for using a LBDDS for poorly soluble drugs, and the use of soft capsules has enabled their commercial success. A high quality, reputable industry partner is highly desirable for the successful, effi cient development, scale-up and commercial manufacturing of soft capsules. It is particularly important to choose a partner that has experience and knowledge to help design an optimal lipid formulation based on the specifi c physicochemical properties of the API during the pre-clinical stages. An added advantage would be using the same partner for scale-up and commercial manufacturing because the process tends to be more straightforward within the same partner entity or network.


Conclusions


The trend for an increasing percentage of pipeline drugs to fall into BCS Class II requires the use of bioavailability enhancement technologies. Lipid-based formulations have many advantages for lipophilic drugs, and they are also the most studied and have the longest history of commercial success. The commercial and clinical success of lipid formulations is due in a large part to the use of soft capsules as their delivery vehicles. Soft capsules do not impact the performance properties of an LBDDS, can be designed for the specifi c API requirements, and can be readily scaled to commercial batch sizes. There are several expert companies in the development and commercial soft capsule market. However, considerations such as history of commercial launches, innovation, and scientifi c knowledge are all important factors when choosing the right partner for successful soft capsule product development and reliable manufacturing supply.


12 | | May/June 2016


References


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